Biomedical subjects

G Monchaux

Publications and source records attributed to G Monchaux.

At least 19 recordsLinked to original sources

PubMed2007

Modeling lung cancer incidence in rats following exposure to radon progeny.

Lung cancer incidence in Sprague-Dawley rats was simulated by a biologically based carcinogenesis model, which is formulated mathematically in terms of a stochastic state-vector model. Doses to the sensitive target cells in the bronchial epithelium of the rat lung were calculated by a stochastic dosimetry model, considering the distinct monopodial branching structure and the crossfire of alpha particles from alveolar tissue to bronchial epithelium. Bronchial and alveolar cellular doses could reasonably be approximated by lognormal distributions, with geometric standard deviations (GSD) between 7 and 10, depending on exposure conditions. Based on a dose-exposure conversion factor of 8.5 mGy WLM(-1) and a GSD of 8, lung cancer incidences were calculated for each cumulative exposure category in the rat inhalation study, consisting of different exposure rates and exposure times. The fair agreement between theoretical predictions and experimental data over the whole exposure range emphasises the necessity to incorporate the full cellular dose distributions rather than their mean values.

Animals↗

PubMed2005

Interaction of smoking and radon in rats: a biologically based mechanistic model.

Data on rats exposed to cigarette smoke before or after exposure to radon are used to estimate smoke-dependent parameters of the biologically based two-stage clonal expansion model. The baseline parameters and the action of radon acting on initiation and promotion were fixed based on earlier work. Cigarette smoke acting on transformation and inducing a reduction of the radon dose to the target cells after a smoking period gives an acceptable description of the data.

Animals↗

PubMed2004

Age-adjustment in experimental animal data and its application to lung cancer in radon-exposed rats.

Procedures for age-adjustment of cancer fractions are proposed which do not require fixed age intervals. The full available information on survival times can then be used, which is especially important in small treatment groups. For incidental cancers a non-decreasing prevalence function and for fatal cancers the Kaplan-Meier estimator is used. In the latter case, the estimated competing risk of the control population is standardized, not its true survival. This makes the technique also applicable to treatment groups with high incidence, which otherwise may give adjusted rates above 100%. In the application part these age-adjustment techniques are used here to study lung cancer in radon-exposed Wistar and Sprague-Dawley rats. The data include a classification in fatal and incidental lung cancers. For fatal lung cancer, the lifetime excess absolute risk (LEAR) at 1 WLM averaged over all exposed groups is 0.67x10(-4) for the Wistar rats, while for the Sprague-Dawley rats it is 0.40x10(-4). For the Sprague-Dawley rats, there are several groups exposed later in life. When the averaging is restricted to animals with start of exposure prior to 150 days of age, the weighted average risk among the Sprague-Dawley rats is 0.79x10(-4). Compared to groups with similar exposures as young adults (up to about 150 days), animals exposed later in life have substantially lower lifetime risks. The Wistar rats include groups with roughly equal exposure rates and ages at start of exposure, but with increasing exposure duration. Within these groupings the LEAR at 1 WLM does not decrease with additional exposure at higher age, as would be expected if the risk from exposures at different ages would be additive.

Administration, Inhalation↗

PubMed2004

Lung tumour risk in radon-exposed rats from different experiments: comparative analysis with biologically based models.

Data sets of radon-exposed male rats from Wistar and Sprague-Dawley strains have been investigated with two different versions of the two-step clonal expansion (TSCE) model of carcinogenesis. These so-called initiation-promotion (IP) and initiation-transformation (IT) models are named after the cell-based processes that are assumed to be induced by radiation. The analysis was done with all malignant lung tumours taken to be incidental and with fatal tumours alone. For all tumours treated as incidental, both models could explain the tumour incidence data equally well. Owing to its better fit, only the IP model was applied in the analysis of fatal tumours that carry additional information on the time when they cause death. A statistical test rejected the hypothesis that a joint cohort of Wistar and Sprague-Dawley rats can be described with the same set of model parameters. Thus, the risk analysis has been carried out for the Wistar rats and the Sprague-Dawley rats separately and has been restricted to fatal tumours alone because of their similar effect in humans. Using a refined technique of age-adjustment, the lifetime excess absolute risk has been standardised with the survival function from competing risks in the control population. The age-adjusted excess risks for both strains of rats were of similar size, for animals with first exposure later in life they decreased markedly. For high cumulative exposure the excess risk increased with longer exposure duration, for low cumulative exposure it showed the opposite trend. In addition, high cumulative exposure exerted lethal effects other than lung cancer on the rats.

Administration, Inhalation↗

PubMed2003

Does mean lung dose calculated after inhalation of alpha emitters actually reflect the risk of induction of malignant lung tumours?

A comparison of incidence of lung tumours in rats after inhalation exposure to aerosols containing alpha emitters which have different physico-chemical properties has been performed. Aerosols of radon and progeny, uranium ore dust, NpO2, PuO2 or Cm2O3 were considered for intercomparison with similar or different particle sizes. Dose-effect relationships for the frequency of malignant lung tumours appear linear up to a few Gy and then become infralinear at higher doses delivered to the lungs. The initial slope of the curves reflects the risk of induction of a lung tumour. The highest slopes of incidence were observed for radon and uranium ore dust (about 70 and 20% Gy(-1) respectively) for which the most homogeneous alpha dose distribution to the lungs is expected. In a general trend, increasing the alpha-activity of deposited particles (higher specific activity of constituent radioisotopes or larger particle size) decreases the risk. The comparison of the reported data shows that the risk per Gy at 'low doses' could vary over more than one order of magnitude depending on the physico-chemical properties of the aerosols.

Actinoid Series Elements↗

PubMed2000

CGH analysis of radon-induced rat lung tumors indicates similarities with human lung cancers.

Epidemiological studies have shown that inhalation of radon, a radioactive gas, is associated with an increased risk for lung cancer. We have developed a model of radon-induced rat lung tumors to characterize cytogenetic and molecular events involved in radon-induced lung tumorigenesis. Using comparative genomic hybridization (CGH), gains and losses of genetic material were investigated in a series of 13 carcinomas and four adenomas of the lung. Frequent losses occurred at 4q12-21, 5q11-33, and 15q, which are homologous to human chromosome (HSA) bands 7q21-36, 1p31-36/9p21-31, and 13q14.1-14.3/3p14.2, respectively. These regions are frequently (30-80%) deleted in human lung cancer and contain tumor suppressor genes or proto-oncogenes such as MET, CDKN2A/p16/MTS1, CDKN2B/p15/MTS2, FHIT, and RB1 or yet to be identified genes. Frequent gains involved 6, 7q34-qter, and 19q; chromosomes 6 and 7 being homologous to human 2p21-25 and 8q21-24 where the MYCN and MYC oncogenes are located. The genetic similarities between rat and human lung cancer suggest common underlying mechanisms for tumor evolution in both species. Moreover, cytogenetic and molecular genetic analyses of radon-induced rat lung tumors could help to better understand the development and progression of radon-induced lung cancer in man.

Adenoma↗

PubMed1999

Lung carcinogenesis in rats after inhalation exposure to (237)NpO2.

The results of several studies of experimental carcinogenesis suggest that, after inhalation of alpha-particle emitters, lung tumor incidence varies depending on the exposure rate and dose distribution in the tissue. In the case of transuranics, the main influencing factor would be the specific alpha-particle activity of the inhaled actinide. To confirm these results, long-term studies were performed using male Sprague-Dawley rats exposed to (237)NpO(2) by inhalation. The initial lung burdens of the animals ranged from 0. 1 to about 7 kBq. The rats were followed during their life span and weighed regularly, and their lung burdens were determined in vivo and at death to estimate the lung dose. At death, the incidence of lung tumors and their malignancy and histological types were analyzed. The analysis revealed a typically linear-quadratic dose response for incidence of malignant lung neoplasm and a differential dose response for various types of tumors. Although these results confirm the influence of the activity of the inhaled actinide oxide, further experiments are needed to be able to compare a more homogeneous population of animals.

Administration, Inhalation↗

PubMed1999

Influence of exposure rate on lung cancer induction in rats exposed to radon progeny.

Animal studies were used in addition to epidemiological studies to investigate the effects of exposure, exposure rate and other factors in predicting risks resulting from exposures to radon progeny. A trend toward increasing tumor risk with decreasing exposure rate was observed in rats exposed at a cumulative exposure varying from about 0.72 J h m(-3) (200 WLM) up to 10.8 J h m(-3) (3,000 WLM) and high exposure rates varying from 25 WLM per week to 500 WLM per week. In contrast, at low cumulative exposure, comparable to lifetime domestic indoor exposures or lifetime occupational exposure in uranium mines, no evidence of an inverse exposure-rate effect was found. Chronic radon exposure at 0.09 J h m(-3) (25 WLM), protracted over 18 months, at a potential alpha-particle energy concentration (PAEC) of 0.042 mJ m(-3) (2 WL), resulted in fewer lung carcinomas in rats than a similar cumulative exposure protracted over 4 to 6 months at a PAEC of 2.1 mJ m(-3) (100 WL). The preliminary results of a new series of experiments carried out at relatively low cumulative exposures of 0.36 J h m(-3) (100 WLM) and PAEC varying from 0.21 mJ m(-3) (10 WL) to 3.15 mJ m(-3) (150 WL) indicate that at cumulative exposures comparable to lifetime indoor or occupational exposures, the risk of lung cancer in rats decreases with decreasing PAEC, i.e. exposure rate. These data suggest that the risk of radon-induced lung cancer results from a complex interplay between cumulative exposure and exposure rate at a given exposure level.

Animals↗

PubMed1996

Intercomparison of measurement techniques used in radon exposure facilities for animals in Europe.

The biological effects of exposure to radon and its progeny are being studied in animals by three laboratories in Europe. The facilities used for such exposures are described, together with the methods used to estimate radon progeny concentrations and the activity deposited in the lungs of exposed animals. As the facilities and methods vary, a series of comparison exercises has been carried out at the three facilities; CEA/COGEMA, Razes, France, TNO, Rijswijk, The Netherlands and AEA Technology, Harwell, U.K. The results of the exercise are presented together with reasons for the discrepancies in results between the groups thus ensuring that estimates of exposure provided by the groups for their studies is directly comparable.

Animals↗

PubMed1994

Effects of lead poisoning of rats during pregnancy on the reproductive system and fertility of their offspring.

1. The effects of lead poisoning during pregnancy were tested on female Sprague-Dawley rats that inhaled 5 mg m-3 lead oxide for 13 days during gestation. At the end of gestation, the respective blood lead levels of dams and fetuses were 71.1 and 83.2 micrograms 100 ml-1, indicating lead poisoning. 2. In the 90 day-old male offspring of the exposed dams, testis weight and histology, and epididymal weight and sperm reserve, were all similar to those of control males. Spermatozoa mobility and morphology were normal. 3. Also similar to control values were the pituitary weight in these male offspring, their plasma FSH, LH and testosterone levels, and the weight of their ventral prostate and seminal vesicles, the targets of the sexual hormones. 4. When male and female offspring of exposed dams were mated, their fertility was normal, with no increase in prenatal death or malformations, and no changes in the size or sex ratio of litters. 5. These results indicate that, under our experimental conditions, lead oxide inhalation by rats during pregnancy did not perturb reproductive function in their male offspring.

Administration, Inhalation↗

PubMed1994

Carcinogenic and cocarcinogenic effects of radon and radon daughters in rats.

It has been previously established that lung cancer could be induced in rats by exposure to radon and radon daughters. Although the oat-cell carcinomas that are common in humans were not found in rats, other histological types of lung carcinomas, especially squamous cell carcinomas and primitive lung adenocarcinomas, were similar to those observed in humans. A dose-effect relationship was established for cumulative doses varying from 25 to 3000 working-level-months (WLM), which was similar for medium and high cumulative doses to that observed in uranium miners. This experimental protocol was also used to study the potential cocarcinogenic effects of other environmental or industrial airborne pollutants such as tobacco smoke, mineral fibers, diesel exhausts, or minerals from metallic mine ores that may act synergistically with radon exposure. In rats exposed to radon and tobacco smoke combined, the incidence of lung cancers was higher by a factor of 2-4 according to the cumulative radon exposure and the duration of tobacco smoke exposure. When mineral fibers were injected intrapleurally, an increased incidence of malignant thoracic tumors was observed in rats exposed to radon and fibers combined, but synergistic effects resulted in additivity. With diesel exhausts or minerals from metallic ores, a slight, nonsignificant increase in the incidence of lung carcinomas was observed compared with rats exposed to radon alone. These results demonstrated that it is possible to establish the potential cocarcinogenic action, showing either multiplicative, additive, or no effect of various environmental or industrial airborne pollutants combined with radon exposure. This radon model is valid for investigating possible interactions between two occupational exposures.

Air Pollutants↗

PubMed1993

Effect of ingestion and inhalation of lead on the reproductive system and fertility of adult male rats and their progeny.

Ninety-day-old Sprague-Dawley rats were intoxicated for 70 d with lead, given either as 0.3% lead acetate in drinking water or by inhalation as 5 mg m-3 lead oxide. Direct or transmitted lead toxicity for the male reproductive system was assessed in the rats and their offspring from pituitary and genital organ weights after exposure, the numbers of Sertoli and germ cells, the number, motility and morphology of epididymal spermatozoa, the levels of plasma testosterone, LH and FSH and fertility tests. Whole blood lead levels were similar after lead ingestion and after inhalation (58.0 +/- 1.7 micrograms dl-1 vs. 51.1 +/- 1.8 micrograms dl-1). Lead acetate ingestion did not affect the reproductive system or fertility of rats. Inhalation of lead oxide did not affect fertility either, but seminal vesicle weight dropped significantly, which might suggest an alteration in the pattern of testosterone secretion. In the male progeny of sires that inhaled lead, the number of epididymal spermatozoa decreased but this did not interfere with fertility. Our results show that for the doses studied, lead inhalation and lead ingestion do not produce strikingly different effects on the male rat's reproductive system. Differences between the present findings and those of others might be due to difference of rat strain or of age at exposure.

Administration, Inhalation↗

PubMed1992

Mesothelioma in rats following intrapleural injection of chrysotile and phosphorylated chrysotile (chrysophosphate).

Pathological effects of asbestos are probably dependent on the size and surface properties of the fibers. Surface-modified chrysotile fibers were injected into the pleural cavity of rats to investigate the potency of the fiber to induce mesothelioma. Chrysotile fibers were modified by a phosphorylation process, resulting in the presence of phosphorus at the fiber surface. Phosphorylated samples were characterized by enhanced durability and reduced affinity for biological macromolecules. Five samples were tested: 1 untreated and 4 phosphorylated. ChrP1, ChrP2 and ChrP3 corresponded to phosphorylated samples obtained by first, second and third passages through an Alpine classifier; Pm was defibrillated ChrP1. The number of fibers per microgram and the size distribution were determined by transmission electron microscopy and classified in 4 size groups. Groups of 35 rats were inoculated with 20 mg of fibers suspended in 0.9% NaCl solution. No mesothelioma was found in the saline controls. All fiber samples were proficient in producing mesothelioma; the percentages were different between groups and untreated chrysotile but not significantly so. The differences may be explained on the basis of the number of fibers injected which were greater than 8 microns in length and less than 0.25 microns in diameter. The findings of a proficiency of long fibers to produce mesothelioma, previously reported by others for glass fibers, could be applied to chrysotile.

Animals↗

PubMed1992

Validity and limitations of animal experiments in assessing lung carcinogenicity of cadmium.

Several cadmium compounds have been observed to induce in rats, but in rats only, a dose-dependent increase in lung cancer. A similar sensitivity to lung cancer induction in both humans and rats can be deduced from a comparison of the histogenesis of tumours and the dose response to radiation, since similar numbers of DNA lesions are produced. Since the carcinogenic action of cadmium is limited to the site of deposition, the toxicokinetics of inhaled particles in human and rodents are discussed in relation to the exposure of the respective target cells in both species. It is stressed that the rat may be much more sensitive to the induction of cancer following the retention of poorly soluble compounds. A comparison of the possible dose-effect response in humans and the dose response in rats showed that the shape of the "dose" response cannot be extrapolated. Finally, clonogenicity and DNA repair of tracheal cells sublethally exposed in vitro to cadmium differ significantly in rats and hamsters. This may explain why hamsters exposed in vivo do not develop tumours.

Animals↗

PubMed1989

Translocation of subcutaneously injected chrysotile fibres: potential cocarcinogenic effect on lung cancer induced in rats by inhalation of radon and its daughters.

Exposure to radon 222 and its daughters has been shown to induce lung cancer in rats. The cocarcinogenic effect of intrapleurally injected mineral fibres in rats which have previously inhaled radon has also been established. The aim of this work was to establish whether a similar process could be induced at a distance from the lungs by subcutaneous injection of chrysotile fibres. Three groups of animals were used: (1) 109 rats which inhaled radon only (dose: 1600 working-level months (WLM]; (2) 109 rats given a subcutaneous injection in the sacrococcygeal region of 20 mg of chrysotile fibres after inhalation of the same dose of radon; and (3) 105 rats injected with fibres only. No mesotheliomas occurred in any of the 3 groups. The incidence of lung cancer was 55% in group 2, 49% in group 1 and 1% in group 3. Statistical analysis using Pike's model showed that the carcinogenic insult was slightly higher in group 2 than in group 1. Electron microscopy analysis of fibre translocation from the injection site showed that less than 1% of injected fibres migrated to the regional lymph-nodes and only about 0.01% to the lungs. After injection, the mean length of the fibres recovered in lung parenchyma increased with time, suggesting that short fibres are cleared by pulmonary macrophages whereas long fibres are trapped in the alveolar walls. Although the high tumour incidence observed in group 1 might have masked the cocarcinogenic effect induced by the fibres, it is possible that this effect can occur only at short distances.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1989

Toxicity of an attapulgite sample studied in vivo and in vitro.

Conflicting data are found in the literature concerning the carcinogenic potency of attapulgite. We tested the carcinogenic potency of French attapulgite in rats, and compared it with 2 chrysotile samples: Rhodesian UICC (Ch A) and short Canadian fibres (Ch C). The mean length of the fibres was 0.77 micron (attapulgite), 3.21 microns (Ch A) and 1.25 microns (Ch C). The mean diameter was 0.06 micron in the 3 samples. The particles (20 mg) in saline were inoculated into the pleural cavity of Sprague-Dawley rats allowed to survive for their full lifespan. The incidence rates of mesothelioma were: 0% (saline controls), 0% (attapulgite), 19% (ChC) and 48% (Ch A). In vitro studies were carried out using cultures of rat pleural mesothelial cells (RPMC). Attapulgite and Ch C did not modify cell growth except at high doses of 10 micrograms/cm2. Unscheduled DNA synthesis (UDS) was detected using [3H]thymidine incorporation in confluent RPMC (GoG1 arrested) and a scintillation method. UDS was stimulated with either Ch A or Ch C at doses ranging from 2 to 10 micrograms/cm2. In contrast, attapulgite did not significantly enhance [3H]thymidine incorporation at doses ranging from 2 to 20 micrograms/cm2. The results show that the attapulgite tested here had no carcinogenic potency. The in vivo and in vitro reactivity of the fibres used in this experiment might perhaps be related to the fibre size; however, other parameters may also be important.

Animals↗

PubMed1988

Asbestos bodies in bronchoalveolar lavage fluid and in lung parenchyma.

Numerical concentrations of asbestos bodies (AB) were measured by light microscopy both in samples of bronchoalveolar lavage (BAL) fluid and in samples of lung parenchyma from 69 patients with suspected asbestos-related diseases who had had lavages and later open lung biopsies or autopsies. Objectives were to study the recovery of pulmonary AB by BAL and the ability of BAL concentrations to predict parenchymal concentrations. BAL and parenchymal concentrations were both spread over 6 orders of magnitude and were positively correlated (r = 0.74 between logarithmic values). It is believed that, by a process of progressive elution, AB firmly adherent to the alveolar wall become suspended in BAL fluid; such suspended bodies represent roughly 2% of all the bodies stored in the portion of lung lavaged. Recovery is associated with great interindividual variations. When a measured BAL concentration exceeds 1 AB/ml, it can be quite confidently predicted, however, that the parenchymal concentration is in excess of 1,000 AB/g and that the patient has experienced a nontrivial asbestos exposure.

Asbestos↗

PubMed1987

Pleural carcinogenic potency of mineral fibers (asbestos, attapulgite) and their cytotoxicity on cultured cells.

The carcinogenicity of several samples of mineral fibers was tested following injection of 20 mg in the pleural cavity of noninbred Sprague-Dawley rats. Three samples of chrysotile asbestos (mean length: 3.2, 2.1, and 1.2 micron) induced mesotheliomas at a rate of 48, 52, and 19%, respectively. The first sample was acid leached prior to intrapleural injection; in that group, the percentage of mesotheliomas was reduced to 25%. Treatment with amosite and crocidolite resulted in the occurrence of 57 and 56% of mesotheliomas. Acid-treatment of amphiboles did not significantly modify the percentage of mesotheliomas. When the Stanton's fiber dimensions were taken into consideration to correlate with mesothelioma incidence, the observed number of mesotheliomas in the chrysotile-treated animals was much lower than that expected, suggesting that other fiber parameters (chemistry, physicochemistry) play a role in the carcinogenicity. Attapulgite fibers (mean length: 0.77 micron) did not induce tumor, and the mean survival time was of the same order as that observed in the control groups. The injection of quartz resulted in no mesothelioma but did result in 6 malignant histiocytic lymphomas (17%) and 2 malignant schwannomas (6%). In vitro experiments did not show strong correlation between cytotoxicity and the carcinogenic potency of these minerals, but the qualitative cellular responses might give some indications on the fiber's potency. In addition, the in vitro effects of the fibers seem to be modulated by their size.

Animals↗